Linoleic Acid–Glucosamine Hybrid for Endogenous Iron-Activated Ferroptosis Therapy in High-Grade Serous Ovarian Cancer
Ying Chen, Xiaoming Liao, Pei Jing, Liangkui Hu, Zengqiu Yang, Yongchao Yao, Chunyan Liao, Shiyong Zhang
Abstract
As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA–GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA–GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA–GlcN. The in vitro study demonstrated that LA–GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA–GlcN at the dose of 50 mg kg–1 achieved a comparable tumor inhibition as doxorubicin hydrochloride (4 mg kg–1) while the overall survival of mice was extended largely due to the low toxicity, and when the dose was increased to 100 mg kg–1, the therapeutic outcomes could be improved further. This dietary hybrid which targets the excess endogenous iron to activate ferroptosis represents a promising drug for HGSOC treatment.